Crystals and process of making 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl—1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

ABSTRACT

The present invention relates to a novel crystals of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid and methods of making the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

CROSS REFERENCE TO RELATED APPLICATION

This Application is a continuation of U.S. application Ser. No.14/171,366, filed on Feb. 3, 2014; which is a continuation of U.S.application Ser. No. 13/987,009, filed on Jun. 24, 2013, which issued asU.S. Pat. No. 8,691,860 on Apr. 8, 2014; which is a divisional of U.S.application Ser. No. 13/175,342, filed on Jul. 1, 2011, which issued asU.S. Pat. No. 8,609,865 on Dec. 17, 2013; which is a divisional of U.S.application Ser. No. 12/168,331, filed on Jul. 7, 2008, which issued asU.S. Pat. No. 7,994,206 on Aug. 9, 2011; which claims the benefit ofpriority to U.S. application Ser. No. 60/948,584, filed on Jul. 9, 2007;all of which are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to novel crystals of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid and methods of making the zwitterion of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid.

BACKGROUND OF THE INVENTION

Delivering an API to a patient requires more than just identifying amolecule and its use. An API must be formulated for delivery to apatient and this formulation (in addition to the API activity) isevaluated by regulatory agencies such as the US Food and DrugAdministration (FDA) and the European Medicines Agency (EMEA). The FDAevaluates the formulation for, among other properties, deliveryproperties, stability, consistency, and manufacturing controls. Animportant factor in determining the properties of a particularformulation is the form of the API. APIs have been known to exist asamorphous forms, crystalline forms, polymorphs, hydrates and solvates.The forms for every API are different. While one particular API may beknown to exist as a polymorph or a solvate, another API may be known toonly exist in amorphous form. This form diversity is important becauseeach different polymorph, solvate, hydrate or amorphous form may havedifferent properties such as stability, solubility, and hygroscopicity.

Some forms of an API can be formulated into an FDA approvableformulation, while other forms lack the required properties to meet thehigh regulatory standards of the FDA. Even if a particular API can existin more than one form suitable for formulation, different properties ofan API form can affect the manufacturing process, shelf stability, routeof administration, bioavailability and other important productcharacteristics. For example, the ability to improve or modulatestability or hygroscopicity can decrease manufacturing costs by reducingthe need for humidity controlled chambers or reducing the need topackage an API in humidity resistant packaging. In addition these samechanges can increase product shelf stability thereby improving productdistribution possibilities and affecting cost. In another example, oneform of an API may have greater bioavailability than another form.Choosing the higher bioavailability form allows for a lower drug dose tobe administered to a patient.

Further, changes to the process of making an API can result in lessprocessing steps, higher purity and lower cost. Such advantages areimportant to the pharmaceutical industry.

5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid is an opoid receptor modulator (mu receptor agonist and deltareceptor antagonist) and may be useful for treating irritable bowelsyndrome, pain or other opioid receptor disorders.5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid and methods of making this molecule are disclosed in US application2005/02033143. Example 9 of US application 2005/02033143 makes thehydrochloride salt of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid. Applicants have discovered a process of making the zwitterion of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid and two novel crystals of this zwitterion. In Applicant's hands,these novel crystals provide improved properties and can be purified athigher purity. Applicant's new process results in improved and lesscostly process manufacturing conditions than the procedure disclosed inUS application 2005/02033143.

SUMMARY OF THE INVENTION

The present invention relates to a Form α and a Form β crystal of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid. The invention also provides for methods of making the zwitterionof5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid. The invention also provides pharmaceutical compositions comprisingthese novel crystals. Compositions and methods of the invention areuseful in the treatment or prevention of a variety of diseasesincluding, among others, irritable bowel syndrome.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates powder X-ray diffraction (PXRD) measurements of arepresentative Form α crystal.

FIG. 2 illustrates a thermal gravimetric analysis (TGA) measurement of arepresentative Form α crystal.

FIG. 3 illustrates a differential scanning calorimetry (DSC) measurementof a representative Form α crystal.

FIG. 4 illustrates a thermal gravimetric analysis (TGA) measurement of arepresentative Form β crystal.

FIG. 5 illustrates a differential scanning calorimetry (DSC) measurementof a representative Form β crystal.

FIG. 6 is the molecular structure of the zwitterion5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid.

DETAILED DESCRIPTION

The present invention is directed to a novel Form α crystal of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid useful for treating irritable bowel syndrome.

In a first embodiment, the present invention comprises a Form α crystalof5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid. In one aspect of this invention, a Form α crystal is characterizedby a powder X-ray diffraction pattern having powder X-ray diffractionpeaks at about 14.0, 14.3, and 14.7 degrees 2-theta. In a further aspectof this invention, a Form α crystal is characterized by a powder X-raydiffraction pattern having powder X-ray diffraction peaks at about 10.2,11.3, 14.0, 14.3, and 14.7 degrees 2-theta. In a still further aspect ofthis invention, a Form α crystal is characterized by a powder X-raydiffraction pattern having powder X-ray diffraction peaks at about 10.2,11.3, 11.8, 14.0, 14.3, 14.7, 16.1, and 18.3 degrees 2-theta. In anotheraspect of this invention, a Form α crystal is characterized by a powderX-ray diffraction pattern having powder X-ray diffraction peakssubstantially as shown in Table 1. In another embodiment, a Form αcrystal is characterized by a powder X-ray diffraction pattern that issubstantially similar to the powder X-ray diffraction pattern of FIG. 1.In a further aspect of this invention, a Form α crystal is characterizedby a thermal gravimetric analysis (TGA) substantially similar to the TGAin FIG. 2. In a further aspect of this invention, a Form α crystal ischaracterized by a differential scanning calorimetry (DSC) measurementsubstantially similar to the DSC in FIG. 3. In one embodiment of thisinvention, a Form α crystal is substantially pure.

In another embodiment, the present invention comprises a method oftreating a mammal suffering from an opioid receptor disorder such asirritable bowel syndrome, comprising administering to said mammal aneffective amount of a Form α crystal of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid. In another embodiment, said mammal is a human.

TABLE 1 Position [° 2θ] 8.0 9.4 10.2 11.3 11.8 14.0 14.3 14.7 15.7 16.116.7 17.1 18.1 18.3 18.7 19.1 20.1 21.5 22.5 22.7 23.7 24.4 25.0 25.726.9 27.8 28.7 29.8

The present invention is also directed to a novel Form β crystal of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid which may be useful for treating irritable bowel syndrome, pain orother opioid receptor disorders.

In a first embodiment, the present invention comprises a Form β crystalof5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid. In one aspect of this invention, a Form β crystal is characterizedby a powder X-ray diffraction pattern having powder X-ray diffractionpeaks at about 11.0, 12.4, and 15.2 degrees 2-theta. In a further aspectof this invention, a Form β crystal is characterized by a powder X-raydiffraction pattern having powder X-ray diffraction peaks at about 11.0,12.4, 14.9, 15.2, and 22.1 degrees 2-theta. In a still further aspect ofthis invention, a Form β crystal is characterized by a powder X-raydiffraction pattern having powder X-ray diffraction peaks at about 11.0,12.4, 14.9, 15.2, 22.1, 25.6, 27.4, and 30.4 degrees 2-theta. In anotheraspect of this invention, a Form β crystal is characterized by a powderX-ray diffraction pattern having powder X-ray diffraction peakssubstantially as shown in Table 2. In another embodiment, a Form βcrystal is characterized by a powder X-ray diffraction pattern that issubstantially similar to the powder X-ray diffraction pattern of FIG. 1.In a further aspect of this invention, a Form β crystal is characterizedby a thermal gravimetric analysis (TGA) substantially similar to the TGAin FIG. 4. In a further aspect of this invention, a Form β crystal ischaracterized by a differential scanning calorimetry (DSC) measurementsubstantially similar to the DSC in FIG. 5. In one embodiment of thisinvention, a Form β crystal is substantially pure.

In another embodiment, the present invention comprises a method oftreating a mammal suffering from an opioid receptor disorder such asirritable bowel syndrome, comprising administering to said mammal aneffective amount of a Form β crystal of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid. In another embodiment, said mammal is a human.

TABLE 2 Position [° 2θ] 8.1 11.0 11.6 12.4 13.1 14.9 15.2 15.5 15.8 16.817.1 17.9 18.7 19.0 19.9 20.4 20.8 21.2 21.6 22.1 22.6 23.3 23.5 24.324.9 25.6 26.0 26.7 27.0 27.4 27.5 28.0 28.5 29.8 30.4 31.8 38.6

Pharmaceutical dosage forms of crystals of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid can be administered in several ways including, but not limited to,oral administration. Oral pharmaceutical compositions and dosage formsare exemplary dosage forms. Optionally, the oral dosage form is a soliddosage form, such as a tablet, a caplet, a hard gelatin capsule, astarch capsule, a hydroxypropyl methylcellulose (HPMC) capsule, or asoft elastic gelatin capsule. Liquid dosage forms may also be providedby the present invention, including such non-limiting examples as asuspension, a solution, syrup, or an emulsion. In another embodiment,the present invention includes the preparation of a medicamentcomprising a crystal of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid. A Form β crystal of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid can be administered by controlled- or delayed-release means.

Like the amounts and types of excipients, the amounts and specific typeof active ingredient in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto mammals. However, typical dosage forms of the invention comprise aForm β crystal of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid, in an amount of from about 0.10 mg to about 1.00 g, from about 0.2mg to about 500.0 mg, or from about 1.0 mg to about 250.0 mg.Non-limiting examples include 0.2 mg, 0.50 mg, 0.75 mg, 1.0 mg, 1.2 mg,1.5 mg, 2.0 mg, 3.0 mg, 5.0 mg, 7.0 mg, 10.0 mg, 25.0 mg, 50.0 mg, 100.0mg, 250.0 mg, and 500.0 mg dosages. The dosages, however, may be varieddepending upon the requirement of the patients, the severity of thecondition being treated and the compound being employed. The use ofeither daily administration or post-periodic dosing may be employed.

The crystals of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid of the present invention may also be used to prepare pharmaceuticaldosage forms other than the oral dosage forms described above, such astopical dosage forms, parenteral dosage forms, transdermal dosage forms,and mucosal dosage forms. For example, such forms include creams,lotions, solutions, suspensions, emulsions, ointments, powders, patches,suppositories, and the like.

The crystals of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid of the present invention can be characterized by the TGA or DSCdata, or by any one, any two, any three, any four, any five, any six,any seven, any eight, any nine, or any ten PXRD 2-theta angle peaks, orby any combination of the data acquired from the analytical techniquesdescribed above which distinctly identify the particular crystal.

The present invention is also directed to a method of isolating andpreparing the zwitterion of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid. In one embodiment, a method of preparing the zwitterion of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid comprises the steps of: combining a strong ionizable acid with5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid to prepare a salt of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid; and washing said salt of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid an inorganic base to obtain the zwitterion of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid. In another embodiment, the invention further comprises the step ofwashing said zwitterion of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}methyl)-2-methoxy-benzoicacid with water. In one aspect of the invention the inorganic base isselected from sodium hydroxide, potassium hydroxide, sodium carbonate,sodium acetate, sodium phosphate. In another aspect of the invention theinorganic base is sodium hydroxide. In a further aspect of theinvention, the ionizable acid is selected from hydrochloric acid,trifluoroacetic acid, sulphuric acid, formic acid, and phosphoric acid.In another aspect of the invention, said ionizable acid is hydrochloricacid.

In one embodiment, a method of preparing the zwitterion of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid comprises the steps of: combining hydrochloric acid with5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid to prepare the hydrochloride salt of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid; washing said salt of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid with sodium hydroxide; and washing said zwitterion of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid with water.

In another embodiment, the invention comprises subjecting the zwitterionof5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid resulting from a process of this invention to recrystallization. Ina further embodiment, such recrystallization is done at a relativehumidity of between 0-40%. In a still further embodiment, suchrecrystallization is done at a relative humidity of greater than 60%.

In one embodiment, the invention comprises crystalline zwitterion of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid prepared by the process of this invention. In a further embodiment,the crystalline zwitterion made by a process of this invention is a Formα crystal. In a still further embodiment, the crystalline zwitterionmade by a process of this invention is a Form β crystal.

In one embodiment, a crystal of this invention has improved stability.

Although the invention has been described with respect to variousembodiments, it should be realized this invention is also capable of awide variety of further and other embodiments within the spirit andscope of the appended claims.

The crystals of the present invention were analyzed using the followingmethods.

Differential Scanning Calorimetry

Both crystals were analyzed using the Perkin-Elmer DSC-7 from ca. 25° C.to 250° C. at a heating rate of 10° C./min.

Powder X-Ray Diffraction

Analysis was performed using a Philips X'Pert Pro MPD diffractometer.Each sample was backloaded and analyzed in a 16 mm sample holder. Usingthe X-Celerator detector, each sample was scanned from 3 to 50° 2θ at astep size of 0.0165° 2θ and a time per step of 10.16 seconds. Theeffective scan speed was 0.2067°/s. Instrument voltage and currentsettings of 45 kV and 40 mA were employed.

The relative intensity of peaks in a diffractogram is not necessarily alimitation of the PXRD pattern because peak intensity can vary fromsample to sample, e.g., due to crystalline mpurities. Further, theangles of each peak can vary by about +/−0.1 degrees, or by about+/−0.05. The entire pattern or most of the pattern peaks may also shiftby about +/−0.1 degrees to about +/−0.2 degrees due to differences incalibration, settings, and other variations from instrument toinstrument and from operator to operator. All reported PXRD peaks in theFigures, Examples, and elsewhere herein are reported with an error ofabout ±0.2 degrees 2-theta. Unless otherwise noted, all diffractogramsare obtained at about room temperature (about 24 degrees C. to about 25degrees C.).

Thermal Gravimetric Analysis

Both crystals were analyzed using the Perkin-Elmer TGA-7 from ca. 25° C.to either 200 or 250° C. at a heating rate of 10° C./min.

The following specific examples illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES Example 1 Preparation of the Zwitterion of5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid

A 1 L three-necked round-bottomed flask equipped with a mechanicalstirrer, addition funnel and a thermocouple was charged withoutagitation. 34.2 g of5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid (see Example 9 of US 2005/0203143), 340 ml of acetone, and 17 ml of204 mmolar concentrated HCl were combined in the flask. The stirring wasstarted and the resulting slurry formed a clear solution. This solutionwas heated to 45° C. under vigorous stirring and aged at thistemperature for a period of two hours. After the completion, thereaction mass was cooled to ambient temperature and the supernatant wasremoved by suction. The vessel along with the residue was rinsed with 20ml of acetone and then removed as previously. 170 ml of water was addedand the reaction mass and was aged under stirring until a homogeneussolution resulted. This solution was then added over a period of ˜½ hrto a solution of 90 ml of 1N NaOH and water. The pH was adjusted to6.5-7.0 accordingly. The resulting slurry was aged for about 2 hrs atambient temperature, cooled to 10-15° C., aged at that temperature forabout 1 hr, and then filtered. The solid was washed with 10 ml water,air-dried for a period of 4 to 5 hrs, and then placed in a vacuum ovenat 50-55° C. until the water content was less than 3%.

Example 2 Preparation of the Form α Crystal

The Form α crystal can be prepared by storing the zwitterion of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid at 0-25% relative humidity for 3 days. Representative PXRD, TGA,and DSC data are shown in FIGS. 1-3 respectively.

Example 3 Preparation of the Form β Crystal

The Form β crystal can be prepared by storing the zwitterion of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid at greater than 60% relative humidity for 3 days. RepresentativePXRD, TGA, and DSC data are shown in FIGS. 1, 4, and 5 respectively.

What is claimed:
 1. A pharmaceutical composition comprising a Form αcrystal of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid.
 2. The pharmaceutical composition of claim 1, wherein said Form αcrystal is characterized by a powder X-ray diffraction pattern havingpowder X-ray diffraction peaks at about 14.0, 14.3, and 14.7 degrees2-theta.
 3. The pharmaceutical composition of claim 1, wherein said Formα crystal is characterized by a powder X-ray diffraction pattern havingpowder X-ray diffraction peaks at about 10.2, 11.3, 14.0, 14.3, and 14.7degrees 2-theta.
 4. The pharmaceutical composition of claim 1, whereinsaid Form α crystal is characterized by a powder X-ray diffractionpattern having powder X-ray diffraction peaks at about 10.2, 11.3, 11.8,14.0, 14.3, 14.7, 16.1, and 18.3 degrees 2-theta.
 5. The pharmaceuticalcomposition of claim 1, wherein said Form α crystal is characterized bya powder X-ray diffraction pattern having powder X-ray diffraction peakssubstantially as shown in Table
 1. 6. The pharmaceutical composition ofclaim 1, wherein said Form α crystal is characterized by a powder X-raydiffraction pattern having powder X-ray diffraction peaks substantiallysimilar to the powder X ray diffraction peaks of FIG.
 1. 7. Thepharmaceutical composition of claim 1, wherein said Form α crystal ischaracterized by a thermal gravimetric analysis (TGA) substantiallysimilar to the TGA in FIG.
 2. 8. The pharmaceutical composition of claim1, wherein said Form α crystal is characterized by a differentialscanning calorimetry (DSC) measurement substantially similar to the DSCin FIG.
 3. 9. The pharmaceutical composition of claim 1, in a dosageform suitable for oral administration.
 10. The pharmaceuticalcomposition of claim 9, wherein the dosage form is a solid.
 11. Thepharmaceutical composition of claim 9, wherein the dosage form isselected from the group consisting of a tablet, a caplet, a hard gelatincapsule, a starch capsule, a hydroxypropyl methylcellulose (HPMC)capsule, and a soft elastic gelatin capsule.
 12. The pharmaceuticalcomposition of claim 9, wherein the dosage form as administered is aliquid.
 13. The pharmaceutical composition of claim 9, wherein thedosage form as administered is selected from the group consisting of asuspension, a solution, a syrup, and an emulsion.
 14. The pharmaceuticalcomposition of claim 9, wherein the dosage form is a tablet.
 15. Amethod of treating a disease in a mammal, wherein the disease is anopioid receptor disorder, comprising administering to said mammal aneffective amount of a pharmaceutical composition comprising a Form αcrystal of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid.
 16. The method of claim 15, wherein the opioid receptor disorderis selected from the group consisting of irritable bowel syndrome, painand a combination of both.
 17. The method of claim 15, wherein theopioid receptor disorder is irritable bowel syndrome.
 18. The method ofclaim 15, wherein the opioid receptor disorder is pain.
 19. The methodof claim 15, wherein the pharmaceutical composition is administered in adosage form suitable for oral administration.
 20. The method of claim19, wherein the pharmaceutical composition is administered in a soliddosage form.
 21. The method of claim 19, wherein the dosage form isselected from the group consisting of a tablet, a caplet, a hard gelatincapsule, a starch capsule, a hydroxypropyl methylcellulose (HPMC)capsule, and a soft elastic gelatin capsule.
 22. The method of claim 19,wherein the dosage form is a tablet.
 23. The method of claim 15, whereinthe mammal is a human.
 24. A pharmaceutical composition comprising aForm β crystal of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid.
 25. A method of treating a disease in a mammal, wherein thedisease is an opioid receptor disorder, comprising administering to saidmammal an effective amount of a pharmaceutical composition comprising aForm β crystal of5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoicacid.
 26. The pharmaceutical composition of claim 24, wherein said Formβ crystal is characterized by a powder X-ray diffraction pattern havingpowder X-ray diffraction peaks at about 11.0, 12.4, and 15.2 degrees2-theta.
 27. The pharmaceutical composition of claim 24, wherein saidForm β crystal is characterized by a powder X-ray diffraction patternhaving powder X-ray diffraction peaks at about 11.0, 12.4, 14.9, 15.2,and 22.1 degrees 2-theta.
 28. The pharmaceutical composition of claim24, wherein said Form β crystal is characterized by a powder X-raydiffraction pattern having powder X-ray diffraction peaks at about 11.0,12.4, 14.9, 15.2, 22.1, 25.6, 27.4, and 30.4 degrees 2-theta.
 29. Thepharmaceutical composition of claim 24, wherein said Form β crystal ischaracterized by a powder X-ray diffraction pattern having powder X-raydiffraction peaks substantially as shown in Table
 2. 30. Thepharmaceutical composition of claim 24, wherein said Form β crystal ischaracterized by a powder X-ray diffraction pattern having powder X-raydiffraction peaks substantially similar to the powder X ray diffractionpeaks of FIG.
 1. 31. The pharmaceutical composition of claim 24, whereinsaid Form β crystal is characterized by a thermal gravimetric analysis(TGA) substantially similar to the TGA in FIG.
 4. 32. The pharmaceuticalcomposition of claim 24, wherein said Form β crystal is characterized bya differential scanning calorimetry (DSC) measurement substantiallysimilar to the DSC in FIG.
 5. 33. The pharmaceutical composition ofclaim 24, in a dosage form suitable for oral administration.
 34. Thepharmaceutical composition of claim 33, wherein the dosage form is asolid.
 35. The pharmaceutical composition of claim 33, wherein thedosage form is selected from the group consisting of a tablet, a caplet,a hard gelatin capsule, a starch capsule, a hydroxypropylmethylcellulose (HPMC) capsule, and a soft elastic gelatin capsule. 36.The pharmaceutical composition of claim 33, wherein the dosage form asadministered is a liquid.
 37. The pharmaceutical composition of claim33, wherein the dosage form as administered is selected from the groupconsisting of a suspension, a solution, a syrup, and an emulsion. 38.The pharmaceutical composition of claim 33, wherein the dosage form is atablet.
 39. The method of claim 25, wherein the opioid receptor disorderis selected from the group consisting of irritable bowel syndrome, painand a combination of both.
 40. The method of claim 25, wherein theopioid receptor disorder is irritable bowel syndrome.
 41. The method ofclaim 25, wherein the opioid receptor disorder is pain.
 42. The methodof claim 25, wherein the pharmaceutical composition is administered in adosage form suitable for oral administration.
 43. The method of claim42, wherein the pharmaceutical composition is administered in a soliddosage form.
 44. The method of claim 42, wherein the dosage form isselected from the group consisting of a tablet, a caplet, a hard gelatincapsule, a starch capsule, a hydroxypropyl methylcellulose (HPMC)capsule, and a soft elastic gelatin capsule.
 45. The method of claim 42,wherein the dosage form is a tablet.
 46. The method of claim 25, whereinthe mammal is a human.